TY - JOUR
T1 - Ligand-Induced modulation of the Free-Energy landscape of G protein-coupled receptors explored by adaptive biasing techniques
AU - Provasi, Davide
AU - Artacho, Marta Camacho
AU - Negri, Ana
AU - Mobarec, Juan Carlos
AU - Filizola, Marta
N1 - Funding Information:
The authors wish to thank Dr. Jennifer M. Johnston for feedback on the manuscript. The computations were supported in part by the National Science Foundation through TeraGrid advanced computing resources provided by Texas Advanced Computing Center under grant TG-MCB080109N.
PY - 2011/10
Y1 - 2011/10
N2 - Extensive experimental information supports the formation of ligand-specific conformations of G protein-coupled receptors (GPCRs) as a possible molecular basis for their functional selectivity for signaling pathways. Taking advantage of the recently published inactive and active crystal structures of GPCRs, we have implemented an all-atom computational strategy that combines different adaptive biasing techniques to identify ligand-specific conformations along pre-determined activation pathways. Using the prototypic GPCR β2-adrenergic receptor as a suitable test case for validation, we show that ligands with different efficacies (either inverse agonists, neutral antagonists, or agonists) modulate the free-energy landscape of the receptor by shifting the conformational equilibrium towards active or inactive conformations depending on their elicited physiological response. Notably, we provide for the first time a quantitative description of the thermodynamics of the receptor in an explicit atomistic environment, which accounts for the receptor basal activity and the stabilization of different active-like states by differently potent agonists. Structural inspection of these metastable states reveals unique conformations of the receptor that may have been difficult to retrieve experimentally.
AB - Extensive experimental information supports the formation of ligand-specific conformations of G protein-coupled receptors (GPCRs) as a possible molecular basis for their functional selectivity for signaling pathways. Taking advantage of the recently published inactive and active crystal structures of GPCRs, we have implemented an all-atom computational strategy that combines different adaptive biasing techniques to identify ligand-specific conformations along pre-determined activation pathways. Using the prototypic GPCR β2-adrenergic receptor as a suitable test case for validation, we show that ligands with different efficacies (either inverse agonists, neutral antagonists, or agonists) modulate the free-energy landscape of the receptor by shifting the conformational equilibrium towards active or inactive conformations depending on their elicited physiological response. Notably, we provide for the first time a quantitative description of the thermodynamics of the receptor in an explicit atomistic environment, which accounts for the receptor basal activity and the stabilization of different active-like states by differently potent agonists. Structural inspection of these metastable states reveals unique conformations of the receptor that may have been difficult to retrieve experimentally.
UR - http://www.scopus.com/inward/record.url?scp=80055099699&partnerID=8YFLogxK
U2 - 10.1371/journal.pcbi.1002193
DO - 10.1371/journal.pcbi.1002193
M3 - Article
C2 - 22022248
AN - SCOPUS:80055099699
SN - 1553-734X
VL - 7
JO - PLoS Computational Biology
JF - PLoS Computational Biology
IS - 10
M1 - e1002193
ER -